Breast cancer cells can physically push their way out of their normal confines to become invasive tumors, new research shows. The findings could point to new ways of preventing cancers from spreading.

Cancers pose the greatest danger when they become invasive and then spread from their originating tissues throughout the body.

The findings, which appear in Nature Communications, could also apply to prostate, liver, skin, and many other cancers that arise from the epithelium, the thin layer of cells that lines the outer edge of many bodily organs. The epithelium is surrounded by a mesh-like structure known as the basement membrane, a thin matrix that encloses, protects, and separates epithelial cells from the surrounding tissue.

Here, an animation shows the process cancer cells use to escape:

The work reveals a previously unknown mechanism cancerous cells use to break through the basement membrane, allowing the tumor to become invasive, says lead author Ovijit Chaudhuri, assistant professor of mechanical engineering at Stanford University.

“Showing how cells can physically invade the basement membrane suggests new therapeutic strategies for blocking invasion,” he says.

Chemical tricks

Previous research had shown that epithelial cancers use chemical tricks to invade nearby tissue. They do this by forming protrusions called invadopodia, which secrete chemicals that act like an acid to burn through the basement membrane.

The new work shows that invadopodia can also use physical force to punch through the basement membrane rather than simply relying on chemicals, known as proteases, says coauthor Katrina Wisdom, a graduate student in Chaudhuri’s lab.

The researchers made their discovery by embedding breast cancer cells in a gelatin-like biogel that mimics the basement membrane—with one major exception. The biogel was not susceptible to protease secretions. Having nullified chemical action as an escape mechanism, the researchers used time-lapse microscopy to track the cancer cells and see whether they could move through the gel. If yes, the cells must have something other than just chemical means of escape.

As it turned out, the cells could burrow through the gel. The time-lapse microscopy revealed how. The images show that cancer cells used their invadopodia like stiff arms to tear tiny holes in the biogel, Wisdom says.

Time and again the cancer cell formed and retracted its invadopodia until the repeated physical battering created an opening large enough for the entire cancer cell to scoot through.

Silly Putty tissue

The experiments revealed a previously unknown process because the biogel more accurately mimicked human tissue, says Chaudhuri. The researchers based their work on the emerging idea that human tissue, especially cancerous tissue, can be somewhat malleable, like Silly Putty, rather than elastic like rubber bands.

Force applied to malleable tissue imparts a permanent effect while elastic materials snap back into shape when force is released. In prior experiments predicated on the assumption of tissue elasticity, the tissue was not susceptible to breaching by a mere physical attack. But in Chaudhuri’s malleable biogel, invadopodia were able to punch out escape tunnels by brute force.

The discovery of a physical role for invadopodia, independent of their previously known protease secretions, might explain why cancer drugs known as protease inhibitors haven’t been effective. After scientists discovered the chemical action of invadopodia, cancer researchers developed these drugs known to stanch protease activity. But Chaudhuri says clinical trials of those drugs proved disappointing.

With the new findings about a physical means of escape, Chaudhuri is working with colleagues on strategies for blocking both the physical and chemical escape mechanisms, in the hopes that this will lead to new ways of preventing cancers from becoming dangerous.

Additional coauthors are from Stanford, Vanderbilt University, Harvard University, and Albert Einstein College of Medicine. The American Cancer Society, the National Institutes for Health, and the National Cancer Institute funded the work.